What Price Screening?—I

^'though the battle is by no means over, acute infec'?us disease has retreated before the advance of ^?dern medicine. The importance of ithe chronic and Generative diseases has increased (accordingly. The r??ts of this type of ill health run deep, for the clinical ^ndrome is the end point of a process which may have een going on for years. Bothwell (1965) has compared ^ advance to progression through the successive parts a spectrum which represents not only the pattern of Issase in a community, but also its progression in the ^dividual in terms of time. In the first part of Bothwell's Pectrum we find those who are free of disease. These be, in the main, the relatively young, although even ^Qngst these there will be some who have a genetic I ^disposition to the development of disease in later ^eThe next part represents the group who are at Pecial risk, perhaps because of the type of environ'Snt in which they live. Some of these, ;n time, pass r?ugh the later stages of early biochemical or Vsical deviations from normal, and early asymptom-

^'though the battle is by no means over, acute infec-'?us disease has retreated before the advance of ^?dern medicine. The importance of ithe chronic and Generative diseases has increased (accordingly. The r??ts of this type of ill health run deep, for the clinical ^ndrome is the end point of a process which may have een going on for years. Bothwell (1965) has compared ^ advance to progression through the successive parts a spectrum which represents not only the pattern of Issase in a community, but also its progression in the ^dividual in terms of time. In the first part of Bothwell's Pectrum we find those who are free of disease. These be, in the main, the relatively young, although even ^Qngst these there will be some who have a genetic I ^disposition to the development of disease in later ^e-The next part represents the group who are at Pecial risk, perhaps because of the type of environ-'Snt in which they live. Some of these, ;n time, pass r?ugh the later stages of early biochemical or Vsical deviations from normal, and early asymptom-Q lc disease. Finally symptoms of ill health begin to ^Cur. When these patients become aware of their th P'0ms and consul their doctors, they have reached lse 'surrender point'. Although the existence of disease c novv recognised, and reparative action?treatment?
'ost ^ *a^en' opportunity for prevention has been Primary prevention consists of removing the funda-ger|tal cause of a disease, so preventing its 'inception.
?condary prevention entails action to disturb the fu'fUence pathogenesis at an early stage, so that del deve'oPmer|t is avoided, or at least markedly tin a^ec'' These are the only categories of true prevenjn So-called tertiary prevention aims only at prevent-9 the further deterioration of an already established Edition.
pr-'n a few instances it is already possible to aim at c'^ary prevention, although it may still be very diffilje to put knowledge into effect. A typical example 0fs 'h the possibility of reducing the number of cases CiQ Carc'noma ?f the bronchus toy doing iaway with syrette smoking (Doll, 1967). Where dangerous sub-Su,nces are used in industry, searches for less harmful w'" 'ead to effective primary prevention, as e rubber industry, where the development of plastic substitutes for the rubber used for insulation in the cable industry has removed the risk of exposure to carcinogenic anti-oxidants. We do not often have enough knowledge to enable us to undertake primary prevention, but we know how to treat and control many conditions, and it is reasonable to think that the earlier application of treatment, in the pre-symptomatic phase, would achieve the goal of secondary prevention.
If this is to be done, it is necessary that an active search be undertaken among apparently well people for those who are in the pre-symptomatic stage. Immediately, several questions demand an answer. Are we able to identify such persons by means of a suitable test? If we are able to identify them, are we able to take effective preventive action? How complex will the sorting process be? How long will it take? What will be the long term gain in terms of disease prevention? It is in the search for the answers to these and similar questions that the nucleus of the present dilemma about screening lies.
Screening for developmental defects in young children has for many years been an important part of the local authority's child welfare work, and has 'included screening for congenital defects such (as dislocation of the hip or occult congenital heart disease, impairment of hearing, or vision, or delay in maturation. Infants are screened for phenylketonuria, either by the phenistix, or, more recently, by the Guthrie, Scriver, or similar tests.
In the adult population, screening for tuberculosis and other pulmonary conditions by means of mass radiography has been going on for many years, and the search among the apparently well for cervical cancer or its precursor, carcinoma in situ, has now become widely established. In Bristol, cervical cytology has been available since 1961, and during 1968 some 9,000 smears were taken?6,083 by local authority doctors in clinics or in a large factory, and 2,873 by general practitioners in their surgeries under N.H.S.
arrangements. In addition an unknown number of smears will have been taken on 'private' patients. Even so, these figures represent only a small proportion of those women who are eligible for the test; Johnson (1968) showed for the Bristol clinical area, that during the previous year the smears received represented only Creening programme were to be mounted in Bristol, much work would be generated, and how much lsease would be uncovered?
?*ganisation and probable results 't would clearly be wise to restrict screening activities those groups in the population most likely to benefit. ri^e search for phenylketonuria must be aimed at the -wborn, the search for carcinoma of the cervix at the 0rnan who is most likely to be in the non-invasive or Thr'y invasive stage of development of the disease, b Us> as far as adult screening is concerned, it might thought that the age group 20 to 74 should be the ' est at which screening should be aimed, and that J ..n this wide range, certain sub-groups should be 'ned for whom some techniques are particularly of The search for early breast cancer by means if Mammography, will be most productive of early cases ^.^orrien aged over 40 are screened, and nullipara p 9ht be considered to be at greater risk, so that rticular efforts should be directed at persuading these attend for examination. Persons with a family history the^'aucoma are more likely to develop the condition .^selves, so that such a history should be given due '9nt when selecting candidates for tests although, in ^ nerai, screening the over forties will result in the sUrKrnUm i-1?1"16^ from glaucoma screening. Factors shn as age' social class, parity, and marital status the>U'd ke taken into consideration when deciding on gr choice of groups eligible for cervical cytology pro-Snd^H185' Bacteriuria's more likely to occur in females, rei the presence or absence of pregnancy may well be ted to the significance of the finding.
proh an exerc'se analogous to that of Last (1963) the p0 ab'e pick-up rates can be applied to the relevant ma ulati?n of the city, and the potential results esti-exeSc!" Table 1 represents the results of such an 9rc>rC'Se' tests have been applied to selected rnjQhPS population, in which the finding rates that * make the exercise worth-while. It is apparent the nat a" those eligible for the tests will attend, and tw0.t?!Tlpirica' assumption has been made that about h^ds will in fact be screened. The population used is that based on the 1966 10% sample census. As a result 'of the initial screening itest a group of individuals is produced who ihave failed the test and need to be more thoroughly investigated. The false positives have to be eliminated by more stringent second tier tests. The false negatives, having, as it were, fallen through the net, iare lost to further action. The proportion of false negatives can be reduced by adjusting the criterion of the screening test, but this almost inevitably reduces its sensitivity so that a larger number of false positives is produced. The diagnostic examinations are much more time consuming than the screening tests, and require specialised expertise for successful completion. Before any screening programme can be undertaken, it is necessary to ensure (that the extra work load generated can be adequately absorbed by the available clinical and laboratory facilities. In addition, facilities are required for the continued supervision of borderline cases which fail to fall neatly into either positive or negative categories. It 'is plain that the provision of screening facilities on a general mass basis for a city the size of Bristol would be a Challenging task. There are in This city some 283,000 persons between the ages of 20 and 74. Assuming that two-thirds of these would make use of any facilities provided, and that the intention would be to achieve a three yearly turnover to allow for re-examination >at regular intervals, it would be necessary to provide for the examination of nearly 63,000 persons per annum. Each attender would take only those tests for which he or she was eligible, thus while all would take the test for diabetes, only about 24,000 would be eligible for the examination for breast cancer in each year. The demand could be met by twelve screening centres deployed around the city. These could, for instance, be parts of Health Centres, and could work on an appointments basis, examining 22 persons per day.

COST
Running costs would obviously be related to the range of examinations offered, and the number of staff employed. The estimates which follow are based on the concept of a centre offering the tests shown in table 2, and staffed by a doctor, a clerk, a typist, two nurses (S.R.N.) and two technicians. The provision of equipment for the various tests would cost in the region of ?300 per centre. This does not of course 'include the cost of X-ray apparatus; or the provision of analytical equipment. Mammography and chest X-rays would be particularly important for the over forty age group, and it would seem reasonable to select three 'or four centres at which these could attend and equip only these centres with X-ray machines. Analysis would best foe carried out at one central laboratory. The largest proportion of running costs would be contributed 'by wages and salaries, which would cost about ?11,000 per annum for each centre. Material and laboratory time for the tests would amount ito another ?2,800. Thus at present day prices, each centre would cost in the region of ?13,800 per annum for staffing, administration and test costs, and to this would be added other costs, such as lighting, tieating, maintenance, etc. The annual cost to the city for all the centres would therefore be lin the region of at least ?165,000 per annum?about ?2.12.0 per individual screened.
Each year, about 320 breast cancer suspects would require investigation by the surgeons, and approximately 37 would eventually need a mastectomy. The gynaecologists would have to investigate about 160 women, and carry out 130 hysterectomies. In the first sweep through the population about 40 early invasive carcinomas of the cervix would come to light annually although after the first few years, assuming that a substantial proportion of women were being reached, it might be expected that the number of invasive cancers would fall. Heavy loads of work would be generated for the diabetic clinics, with the prospect of some 2,230 glucose tolerance tests a year, and ophthalmic clinics, with the investigation of about 1,560 ocular hypertensives. In these two specialties also, there would be a large number of bordertiners who would require observation for a prolonged period.
It is quite apparent that such demands would easily swamp existing facilities. There would be a need to provide for at least some of the second tier tests to be carried out as an extension of the work of the screening clinics. This would call for extra specially trained staff to carry out this work. For instance, tonography and ophthalmoscopy could be carried out on those who failed the preliminary screening tests for 'glaucoma at a borderline level, and similarly additional tests such as full glucose tolerance tests could be carried out on 'borderline diabetics.' If such second tier tests were done by doctors associated With the initial screening clinics, and only the certain failures from these tests went forward to the hospital clinics, a great deal of the potential load on the consultant clinics would be diverted.
The efficient 'handling of the records of such a large part of the population of the city, with provision for the accumulation of the results for each individual, and recall for second tier examinations, or simply for further screening sessions as the years passed, would require the use of a computer.
No programme of this sort could possibly foe contemplated without a clear indication that the return, however it might be measured, would be commensurate. We need to know what would really be achieved in terms of the prevention of 'disease. What would this represent in the future? 'Less expenditure on the treatment of established disease? Fewer demands on supporting social services? A healthier and more productive population? Such assessments can only be made on the basis of experience with screening projects which 'are already established.

PAST EXPERIENCE
There li's nothing particularly new about the concept of screening for occult disease. Screening for hookworm, malaria, and other infectious disease was carried on from 1910 in (the U.S.A., and a manual of 'suggeS' tions for (the conduct of periodical examinations of apparently healthy persons' was issued by the American Medical Association iin 1927. Mass radiography techniques were developed from the early 1930's, and mass miniature radiography clinics were (introduced by the Ministry of Health 'in 1943. tin many ways mass radiography represented an ideal method of screening, f?r it was a way of detecting a relatively common disease which was undeniably important. The test used was capable of finding the condition sought in its early stages, before it had become symptomatically apparent to ithe victim. The disease was capable of treatment which would arrest and even reverse the pathologic^' process, and the test was rapid, easy to apply, and acceptable to ithe patient. It is not surprising that attempts were made to extend the concept in other directions. Diabetes detection was attempted in the U.S.A. in the early forties (Gates, 1942;Wilkerson and Krai I' 1947). Early attempts in the United Kingdom were often attempted as extensions of the activities of Mass Radio* graphy Units?for example, Burn (1956). Most studie5 showed that an unknown diabetic existed for each one already recognised. Reid (1960) demonstrated tha 19.7% of a group of 352 diabetics had suffered con' tinuous symptoms for over a year before the diagnoses was established. The Bedford study (Sharp, Butterfiel" and Keen, 1964) 'has been the largest definitive study of diabetes detection in this country. Four per cent 0 25,700 specimens of urine were positive to the clin'isti^ test for glucose, and these persons were asked to undergo glucose tolerance tests. Just under a third 0 them were found to have diabetes, the criterion beinS a blood sugar level of 120 mg % or more two hour5 after a 50 G glucose load. However, in the course 0 the same study 70 of 543 aglycosurics who were ran* domly subjected to a glucose tolerance test were foun to have abnormalities of glucose tolerance. This threVV grave doubts on t'he reliability of simple urine testing as a screening test, a finding 'later reinforced by ^ results of a study by the College of General Prac*' tioners (1962).
The distribution 'of two hour blood sugar levels 1 continuous, and there is no definable cut-off point resulted in the identification of a similar borderline 9roup of ocular hypertensives whose fate was uncertain, and this has been the experience in all sub-Sequent studies. Graham (1966) ;has expressed considerable doubts about the use of tonometry alone as a screening test, and the combination of tonometry ^'th ophthalmoscopy, or with visual field screening (using rapid methods) has been suggested in the Search for a more reliable 'test. The phenistix test for Phenylketonuria was widely applied in the United ^'ngdom from 1959 onwards. By 1963, 'the first doubts ^>out its reliability were being expressed (Scott, 1963;Woolf, 1967) and in due course Stephenson and ^cBean (1967) (Wilson, 1968). he failure, so far, of the cervical cytology programmes ln British Columbia and New Zealand to produce a ^cognisable reduction in mortality from carcinoma of 5 cervix has been well documented (Green, 1966 Is the cost of case finding (including diagnosis and treatment of patients diagnosed) economically balanced in relation to possible expenditure on medical care as a whole?
10. Will case finding be <a continuous process, rather than a 'once and for all' event?
The application of these questions to the majority of the screening procedures presently available opens up large gaps in current knowledge, and the need is therefore for carefully controlled investigations, related to conditions selected for their potential suitability for screening programmes, with the object of deriving the missing answers. It is particularly impoitant that screening does not become a widespread and accepted technique until it is based on firm, scientifically acceptable foundations. Otherwise there is great danger that it will no longer be ethically acceptable to carry out the very investigations necessary to establish its credibility. Already, it is plain that a controlled trial of the efficacy of treatment of phenylketonuria would be unthinkable, as would a controlled study of the outcome of treating carcinoma in situ. New screening projects must therefore be set up from the outset as specific research ventures, with the intention of fully documenting and following up all cases, whether an abnormality is detected at screening or not. Where abnormalities are detected, controlled trials of the efficacy of treatment? such as that currently being carried out by Keen? are required. These will define both the natural history of the disease from its earliest stage of inception and the effect, if any, of early treatment upon the progress of the pathological process. Such investigations must be undertaken with due consideration for their anxietyprovoking potential, and in full knowledge of the ethical considenations involved. McKecwn (1968) has rightly pointed out that when a doctor or public health medical authority takes the initiative in investigating the possibility of illness or disability in persons who have not complained of signs or symptoms "there is then a presumptive undertaking, not merely that abnormality will be identified if it is present, but that those affected will derive benefit from subsequent treatment or care. This commitment is at least implicit, and except for research and the protection of public health ... no one should be expected to submit to the inconvenience of investigation or the anxieties of case finding without the prospect of medical benefit. The obligation exists even when the patient asks to be screened, for his request is then based on the belief that the procedure is of value, and if it is not, iit is for medical people to make this known." The time is ripe, not for great city-wide schemes of mass population screening, but for studies of the effects and benefits, as well as the feasibility, of the method on smaller, well defined populations. These would be research projects, and must be clearly understood to be such. Such projects might be undertaken within a general practice, where a well defined population, listed on an accurate age/sex register, is available. Or they may be undertaken within the context of occupational health schemes?such a study within the Occupational Health Service of the Corporation of Bristol 'is in the early stages of development. Adequate research is the immediate price of effective and ethically acceptable screening. Unless this lis paid in full at the outset, there can be no real progress in this, as in any other, field of medicine. The cost benefit analysis can safely be left to the future, when we may hope to have better evidence upon which to base our estimations.